Sorbent for a dialysis device and dialysis system

ABSTRACT

The invention relates to a sorbent for removing metabolic waste products from a dialysis liquid, the sorbent comprising a soluble source of sodium ions. The sorbent comprises an ion exchange system which converts urea to ammonium ions and which is configured to exchange ammonium ions for predominantly hydrogen ions and to exchange Ca, Mg, and K for predominantly sodium ions. The soluble source of sodium ions overcomes an initial drop in sodium concentration in regenerated dialysate. When used in conjunction with an infusion system configured to utilise exchange of Ca, Mg and K for sodium during dialysate regeneration a desired sodium ion concentration can be maintained.

FIELD OF INVENTION

The present invention relates to a sorbent for dialysis as well as to asorbent system for regenerative dialysis which may be, but is notlimited to, haemodialysis, peritoneal dialysis, liver dialysis, lungdialysis, water purification and regeneration of biological fluids.

BACKGROUND

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Dialysis is the separation of particles in a liquid on the basis ofdifferences in their ability to pass through a membrane. In medicine,the term refers to the clinical purification of blood as a substitutefor the normal function of the kidney. In particular, dialysis is usedto replace kidney function for patients suffering from renal dysfunctionor failure. The term may also refer to the purification of otherbiological fluids including ascites, urine, and haemofiltrate. Thepurification is typically done by contacting a biological fluid, such asblood, with a purifying liquid, such as dialysate, through asemipermeable membrane. This process removes excess water, electrolytesand waste toxins from the body, therefore ensuring their concentrationsare within physiological ranges. Most commonly, the purifying fluid(typically dialysate) is only used one single time, and is simplydiscarded as “spent dialysis fluid” after it has contacted thebiological fluid (typically blood) once. This is referred to as“single-pass” dialysis. Sorbent-based regenerative dialysis, on theother hand, is a process that recycles a dialysis fluid after it hasbeen used to purify a biological fluid. The process removes unwantedsubstances from the spent dialysis fluid (regeneration) and replacesdesired substances (reconstitution) to produce a “fresh dialysis fluid”,which is then contacted again with the biological fluid to continue thedialysis process.

The predominant form of dialysis used for patients with end-stage renaldisease is in-centre single-pass haemodialysis. Haemodialysis involvesthe use of an extracorporeal system for removing toxins directly fromthe patient's blood by passing through a filtering unit, or dialyser. Inconventional single-pass haemodialysis processes, patients areimmobilised for the duration of the dialysis, which may take many hours.The therapy requires the provision of large volumes of purified(ultrapure) water for preparation of dialysate, which is used once andimmediately discarded.

The other form of dialysis is peritoneal dialysis, which is commonlyapplied in Continuous Ambulatory Peritoneal Dialysis (CAPD) andAutomated Peritoneal Dialysis (APD). In CAPD, fresh dialysate is infusedinto the patient's abdominal (peritoneal) cavity where, by means ofdiffusion, metabolic waste and electrolytes in the blood are exchangedwith the dialysate across the peritoneal membrane. To allow sufficientdiffusion of the electrolytes and metabolic wastes to occur, thedialysate is typically retained in the peritoneal cavity for a couple ofhours before removal and replacement of the spent dialysate with freshdialysate. Major drawbacks of CAPD include a low level of toxinclearance and the need to continuously replace the spent dialysate,which can be disruptive to the patient's daily activities. APD functionssimilarly to CAPD, except that it allows the dialysis to be performed atnight or while the patient is resting, and allows the dialysate to beexchanged and replaced automatically.

Similarly to single-pass haemodialysis, both CAPD and APD requirecomparatively large volumes of dialysate, which limits the patient'sfreedom and mobility. There are devices that regenerate used dialysatefrom haemodialysis and/or peritoneal dialysis, as opposed to discardingit, to reduce the quantity of liquid used. The dialysate can beregenerated by passage through a sorbent that eliminates uremic toxinsand excess electrolytes from the solution. For example, the originalREDY (REcirculating DYalysis) Sorbent System includes a sorbentcartridge having five layers through which dialysis solution containinguremic waste metabolites flows in order to be regenerated.

A number of sorbent dialysis systems, such as the REDY, Allient or AWAKsorbent systems, employ a urease to convert urea, which (unlike othermetabolic wastes such as creatinine and uric acid) is not readilyadsorbed by activated carbon, into ammonium ions and bicarbonate ions.In the REDY system, a first layer consisting of activated carbon andhydrous zirconium oxide acts as a scavenger layer, and preventsinactivation of the urease by trace metal contaminants. The second layercontains urease adsorbed onto alumina particles. The third layerconsists of buffered zirconium phosphate, which acts as a cationexchanger. As discussed in Drukker W. and van Doorn A. W. J. (1989)Dialysate Regeneration. In: Maher J. F. (eds) Replacement of RenalFunction by Dialysis. Springer, Dordrecht, the zirconium phosphate isloaded with hydrogen ions and sodium ions in a ratio of 1:8. Ammoniumions, along with calcium, magnesium and potassium ions, are exchangedfor hydrogen and sodium ions. The released hydrogen ions are partiallybuffered by the bicarbonate but there is a drop in pH due to release ofhydrogen ions, a drop in carbonate concentration as a result of thebuffering but, after an initial drop, a gradual increase in sodium ionconcentration in the dialysate due to exchange of ammonium, calcium,magnesium and potassium ions for sodium ions. The fourth layer consistsof hydrous zirconium oxide, which acts as an anion exchange resin andreplaces phosphate in the dialysate with acetate. Finally, an activatedcarbon layer adsorbs creatinine, uric acid and other metabolites.

US patent publication no. 2010/0078387 discloses a sorbent cartridgecomprising a combination of acid zirconium phosphate and alkalinehydrous zirconium oxide capable of restoring the balance of Na⁺ and HCO₃⁻ in spent dialysate to the levels found in fresh dialysate. In apreferred aspect the system relies on reducing pH and Na⁺ in regenerateddialysate to a low level, and reducing HCO₃ ⁻ to zero. A NaHCO₃reinfusion system then brings pH, Na⁺ and HCO₃ ⁻ to desired levels.

PCT patent publication no. WO 02/43859 discloses a sorbent cartridgecomprising layers of sodium zirconium carbonate and zirconium phosphate.The sodium zirconium carbonate layer adsorbs phosphate, while thezirconium phosphate adsorbs ammonia, Ca²⁺, Mg²⁺, K⁺ and toxic heavymetals present in the spent dialysate fluids. The sorbent exchangeprofile is influenced by introducing a new compound, sodium zirconiumcarbonate, which acts to correct pH and release bicarbonate.

U.S. Pat. No. 6,818,196 discloses a method of making zirconium phosphatewhich involves treating sodium zirconium carbonate with caustic soda(sodium hydroxide) to form an alkaline hydrous zirconium oxide. This issubsequently heated and mixed with phosphoric acid to yield an acidiczirconium phosphate, which is further titrated with caustic soda toobtain the desired zirconium phosphate. The aim is to produce betterquality zirconium phosphate for use in REDY sorbent cartridges.

U.S. Pat. No. 7,241,272 relates to the use of a resin bed in a cartridgefor removing metabolic waste materials. It comprises at least fourlayers — a urease layer, a layer of zirconium phosphate, a layer ofzirconium oxide and a layer of carbon. The zirconium phosphate layer,which contains two counter-ions Na⁺and H⁺, can absorb NH₄ ⁺, Ca²⁺, Mg²⁺and Na⁺. Release of the counter-ions is determined by the dialysate pHand the current loading state (pH) of the resin. The Na⁺ions are alsoreleased in exchange for NH₄ ⁺, Ca²⁺, Mg²⁺ and K. Substantialfluctuations in pH, Na⁺and bicarbonate levels are apparent in mostfigures.

U.S. Pat. No. 8,580,112 describes a dialysis system which uses a sorbentcartridge comprising sodium zirconium carbonate, zirconium phosphate orother ammonia adsorbents, alumina, zirconium oxide, alumina supportedurease, and granular activated carbon to remove waste materials. Thedialysis system has a feedback control system which relies onconductivity sensing to measure sodium levels and controls theconcentration of sodium ions in regenerated dialysate by adding water asdiluent when required.

PCT publication no. WO 2009/157877 discloses a sorbent for removingmetabolic waste products from a dialysis liquid. The sorbent comprisesof a layer of immobilized uremic toxin-treating enzyme particlesinter-mixed with cation exchange particles. However, there are stillsubstantial pH, Na⁺ and bicarbonate fluctuations, and the effect ofcalcium, magnesium and potassium ions is not discussed.

PCT publication no. WO 2005/123230 relates to a system that contains twosorbent-type cartridges in which one is for breaking down urea andreleasing Na⁺, while the other is for binding Na⁺. The sorbent thatdecomposes urea and releases sodium comprises one or more layers ofactivated carbon, urease, zirconium phosphate and/or zirconium oxide.The sorbent that binds Na⁺ can be a mixed bed ion exchange resin whichcomprises a cation exchange resin and an anionic exchange resin that aremixed and contained in the same housing. Dialysate sodium control isachieved by optionally including or bypassing the second sorbent. Thesystem relies on feedback control by conductivity sensing to accuratelycontrol sodium.

PCT publication no. WO 2007/103411 discloses a dialysis system having areplaceable cartridge which uses cation rejecting membranes to rejectNa, Ca, Mg and K while the remaining waste components diffuse across themembrane to contact a purification layer that removes heavy metals,oxidants and other uremic waste metabolites; a urea removal layer thateliminates urea from the solution but rejects cations; and an ionexchange layer that removes phosphate and sulfate. This presumably makesthe purification system independent of Ca Mg and K concentration andpresumably also prevents Na release in exchange for NHa. Na profile isthus also expected to be independent of urea concentration.

US patent publication no. 2013/0213890 discloses a modular haemodialysissystem with a sorbent cartridge that contains at least an activatedcarbon material for absorbing uremic waste and creatinine, and azirconium oxide material to absorb phosphates from the dialysate. Whileenabling removal of urea, the cation exchange process releases sodiumand hydrogen into the dialysate in a stoichiometric fashion. In order tomaintain a stable composition of the dialysate, sodium ion concentrationmust be reduced either by absorption of sodium ions or by dilution.Further, the generation of carbon dioxide and hydrogen ions leads to pHinstability of the dialysate that can require infusion of bicarbonate orother means to adjust pH.

US patent publication no. 2013/0199998 relates to a haemodialysis systemhaving a controlled compliance dialysis circuit with a pump to controlthe flow of fluid between the dialysis circuit and the extracorporealcircuit across a dialysis membrane. The Na⁺concentration is monitored bymeasuring the conductivity of the dialysate and control is achieved bydilution.

There are problems associated with currently known methods. The Na⁺concentration in the dialysate initially falls but then graduallyincreases for the duration of the dialysis due to the exchange processesduring dialysate regeneration. The gradual concentration change is thentypically centred around a target concentration which is physiologicallyacceptable. For example, regenerated dialysate in the REDY system istypically characterised by sodium concentrations which increase fromaround 100 mEq/L to around 160 mEq/L over the period of the dialysiswith an average of around 140 mEq/L. Therefore, while the Na⁺concentration might average the target concentration of 140 mEq/L whenthis approach is adopted, for most of the dialysis the Na⁺ concentrationis either above or below optimum.

Most commonly known sorbents, e.g. the REDY sorbent, are selected todeliver an approximately neutral overall sodium balance, and neutral pHconditions. This is done by pre-conditioning the sorbent materials suchthat both ammonium, as well as Ca, Mg and K are partially exchanged toprotons, and partially exchanged to sodium (e.g. Drukker on REDYsorbent: H/Na loading ratio 1:8). There is an initial phase of lowdialysate sodium concentration, followed by a gradual increase indialysate sodium concentration and ending with a high final dialysatesodium concentration. Over the course of the entire therapy, the sodiumconcentration averages approximately at the desired physiological targetsodium concentration. The sorbent and its exchange behaviour is designedto produce as neutral pH conditions as possible, while at the same timeavoiding extreme low and extreme high sodium concentrations. In order toproduce this exchange behaviour, the sorbent material is pre-conditionedand “pre-loaded” with sodium during synthesis. This is then oftencombined with a customised starting diaysate bath. The pre-loading maybe applied to both, cation and anion exchangers. Further, some sorbentsuse chemical modifications of one of the ion exchange materials, such ase.g. the use of sodium zirconium carbonate as anion exchanger instead ofhydrous zirconium oxide. All these modifications have in common thatthey are not directed at the differentiation of exchange behavioursbetween ammonium and other dialysate cations. They are merely directedat buffering pH fluctuations while at the same time preventing extremesodium concentrations, without taking specific exchange selectivitiesinto account.

Other known sorbents are selected to provide exchange properties whichare more extreme, having either a very low sodium loading and providingapproximately quantitative exchange of ammonium, Ca, Mg and K toprotons, or having a very high sodium loading and providingapproximately quantitative exchange of these cations for sodium. Thesesystems require feedback-controlled infusion systems to correct theresulting extremely low or extremely high sodium concentrations inregenerated dialysate. This may be done by feedback-controlled mixing ofthe two types of regenerated dialysates (low Na and high Na), or byfeedback-controlled infusion of NaHCO₃ (low-Na regenerated dialysate) ordilution with water (high Na regenerated dialysate).

None of these sorbents is selected for differential exchange behaviourfor ammonium, and for Ca, Mg and K, respectively. All of these cationsare generally assessed jointly, with the assumption of similar exchangeratio H/Na for all of these cations, which is jointly determined by theNa pre-loading of the sorbent during synthesis. In fact, the possibilityof such differential exchange behaviour and its exploitation to producea desired sodium exchange profile has previously not been recognised.

Rather, the ion exchange systems are pre-loaded with sodium in a waythat produces the intended exchange profile (either equilibrated at aphysiological equilibrium concentration, or brought to either extreme ofcomplete exchange to proton, or sodium).

Other systems attempt to counter this gradual change with feedbacksystems, measuring the sodium concentration and then administering aconcentrate solution or water to increase or decrease the final sodiumconcentration. Such feedback systems are complicated, costly, and proneto malfunctions. They typically rely on conductivity measurements whichare known to be problematic and have limited accuracy. Further, theycontribute to an increased physical size of the systems, and increasednumber of disposable components.

Existing sorbent systems are characterised by a substantial degree ofsodium release in exchange for ammonium, potassium, calcium andmagnesium. This leads to a steady addition of sodium to regenerateddialysate, which in turn results in a steady increase of the dialysatesodium concentration. Concurrently with sodium, other constituentconcentrations, such as bicarbonate and chloride concentration, are alsopoorly controlled. This may result in undesirable and potentiallyharmful conditions for the patient, such as e.g. hyperchloremicacidosis. This is particularly relevant when chloride salts of Ca, Mgand K are used for reconstitution of spent dialysate. Some previoussorbent systems, such as e.g. the REDY system, used acetate saltsolutions of Ca/Mg/K to counter or ameliorate such undesirable effects.However, these acetate salt solutions are known to be problematic forthermal sterilisation processes. Existing sorbent systems are thereforelimited to use non-sterile solutions of these salts. Other salts of weakacids, such as bicarbonate or lactate salts have insufficient solubilityto be of practical use for dialysate reconstitution.

The key problem with the above systems is that the selectivity ofexchange behaviour between ammonium, and the other dialysate cations,Ca, Mg and K, has not been recognised, and hence the potential ofexploiting such a selectivity in sorbent-based dialysate regenerationhas not been recognised. The prior art goes to great lengths to strike abalance between low pH in regenerated dialysate and high sodium release.This is done by pre-loading the sorbents with Na during synthesis,providing barely acceptable pH profiles at the cost of significantsodium release. The patients are thus exposed to imperfect orpotentially even harmful dialysate compositions for most of thedialysis.

SUMMARY

The present invention provides a sorbent for removing metabolic wasteproducts from a dialysis liquid, the sorbent comprising a soluble sourceof sodium ions.

The soluble source of sodium ions may be present as a homogeneousmixture with at least one of: (a) uremic toxin-treating enzyme particlescomprising a uremic toxin-treating enzyme immobilized on a solidsupport; (b) cation exchange particles configured to exchange ammoniumions for predominantly hydrogen ions and to exchange essential cationspredominantly for sodium ions; and (c) anion exchange particles

Accordingly, the present invention provides a sorbent for removingmetabolic waste products from a dialysis liquid, the sorbent comprisinga homogeneous mixture of: (a) uremic toxin-treating enzyme particlescomprising a uremic toxin-treating enzyme immobilized on a solidsupport; (b) cation exchange particles configured to exchange ammoniumions for predominantly hydrogen ions and to exchange essential cationspredominantly for sodium ions; and (c) anion exchange particles, andfurther comprising a soluble source of sodium ions.

Also provided is a process of preparing a sorbent comprising mixing asoluble source of sodium ions and at least one of: (a) uremictoxin-treating enzyme particles comprising a uremic toxin-treatingenzyme immobilized on a solid support; (b) cation exchange particlesconfigured to exchange ammonium ions for predominantly hydrogen ions andto exchange essential cations for sodium ions; (c) anion exchangeparticles; and (d) organic compounds absorber particles, and containingthe mixture.

In a further aspect there is provided a sorbent which hydrolyses urea toammonium and bicarbonate, and binds ammonium predominantly in exchangefor protons. The protons exchanged for ammonium combine withbicarbonate, and the resulting carbonic acid is released as CO₂. Thesorbent thus removes urea by conversion to CO₂. This produces repeatablechemical conditions in regenerated dialysate, which are independent ofthe spent dialysate urea concentration.

In a further aspect there is provided a sorbent which predominantlybinds essential cations in exchange for sodium ions.

In a further aspect there is provided there is provided a sorbent which(a) hydrolyses urea to ammonium and bicarbonate, and (b) binds ammoniumpredominantly in exchange for protons and binds essential cationspredominantly in exchange for sodium ions.

In a further aspect there is provided there is provided a sorbentcartridge comprising a sorbent as described herein housed in acartridge.

In a further aspect there is provided there is provided a dialysissystem for treating and recycling dialysate, the system comprising asorbent cartridge as described herein which releases a predicted amountof sodium following ion exchange in the sorbent, a conduit for conveyingspent dialysate from a source of spent dialysate to the sorbentcartridge, a conduit for conveying regenerated dialysate from thesorbent cartridge to the source of spent dialysate, and an infusatesystem for dosing an infusate solution comprising essential cations tothe regenerated dialysate such that the solution combines with thepredicted release of sodium ions from the sorbent cartridge to generatea predetermined dialysate sodium concentration.

The sorbent cartridge comprises a sorbent as described herein, whichpredominantly binds Ca, Mg and K in (stoichiometric) exchange for Na.The concentration of Ca, Mg and K in spent dialysate before sorbentregeneration is subject to only minor (absolute) fluctuations, and islargely controlled by the predetermined concentration generated throughaddition of infusate solution during the previous regeneration andreconstitution process. The essential cations are generally introducedin an infusate solution. The concentration of the essential cations inthe infusate solution is chosen such that it matches the increase in Nareleased from prior exchange of Ca, Mg and K from spent dialysate on thesorbent. The combination of regenerated dialysate with this matchinginfusate solution results in the generation of a desired (predetermined)sodium concentration. Depending on the choice of infusate compositionand infusion rate, the system can be adapted to produce specific sodiumprofiles, or maintain constant sodium concentration in regenerateddialysate without the need for a feedback control system.

Accordingly, in another aspect there is provided there is provided aprocess for regenerating dialysate in a dialysis process, comprisingrepeating the steps of:

(a) conveying spent dialysate from a source of spent dialysate to asorbent which (a) hydrolyses urea to ammonium and bicarbonate, and (b)binds ammonium predominantly in exchange for protons and binds essentialcations predominantly in exchange for sodium ions, to produceregenerated dialysate;

(b) introducing essential cations to the regenerated dialysate toreconstitute the dialysate; and

(c) conveying reconstituted dialysate from the sorbent to the source ofspent dialysate;

characterised in that a predetermined concentration of sodium ions isgenerated following ion exchange in the sorbent.

In yet another aspect there is provided there is provided a kitcomprising a sorbent as described herein and an infusate comprisingsalts of essential cations.

DRAWINGS

In order that the disclosure may be readily understood and put intopractical effect, reference will now be made to embodiments asillustrated with reference to the accompanying figures and the examples.The figures together with the description serve to further illustratethe embodiments of the invention and explain various principles andadvantages.

FIG. 1 is a schematic diagram showing a possible interpretation of theion exchange characteristics of a cation exchanger in accordance withthe current invention.

FIG. 2 is a schematic diagram illustrating a single loop dialysis systemfor testing sorbents.

FIG. 3 is a schematic diagram illustrating a double loop dialysis systemfor testing sorbents.

FIG. 4 is (a) a graph showing the effect of patient urea level on sodiumion concentration and (b) is a graph showing the effect of dialysateurea and Ca/Mg/K on sodium ion concentration.

FIG. 5 is a graph showing the sodium concentration of simulated patientbiological fluid before and after purification in a double loop dialysissystem (“Blood Upstream” and “Blood Downstream”), as well as the sodiumconcentration in regenerated and reconstituted dialysate (“DialysateUpstream”) according to the present invention.

FIG. 6 is a diagram showing (a) the initial sodium drop and subsequentgradual rise in sodium concentration in conventional sorbent-baseddialysis systems, (b) the effect of a sorbent modification to overcomethe initial sodium drop without alteration to the gradual rise in sodiumconcentration, (c) the effect of system modification to address both theinitial sodium drop and the subsequent gradual rise in sodiumconcentration to provide a steady sodium concentration throughout thedialysis, and (d) the effect of system modification to address both theinitial sodium drop and the subsequent gradual rise in sodiumconcentration to provide a gradual reduction in sodium concentrationduring the dialysis.

FIG. 7 is a graph showing the effect of patient urea level on carbonateconcentration.

FIG. 8 is a graph showing the effect of patient urea level on chlorideconcentration.

FIG. 9 is a graph showing the effect of patient urea level on pH.

FIG. 10 is a graph showing the effect of dialysate urea and Ca/Mg/K onbicarbonate concentration.

FIG. 11 is a graph showing the effect of dialysate urea and Ca/Mg/K onchloride concentration

FIG. 12 is a graph showing the effect of dialysate urea and Ca/Mg/K onpH.

FIG. 13 is a graph showing the effect of sodium bicarbonate in thesorbent on sodium ion concentration.

FIG. 14 is a graph showing the effect of sodium bicarbonate in thesorbent on bicarbonate concentration.

FIG. 15 is a graph showing the effect of sodium bicarbonate in thesorbent on chloride concentration.

FIG. 16 is a diagram illustrating a dialysis process in accordance withthe present invention.

DESCRIPTION

The present invention relates to a sorbent for removing metabolic wasteproducts from a dialysis liquid. In particular the invention relates toa sorbent for removing metabolic waste products from a dialysis liquid,the sorbent comprising a soluble source of sodium ions. As describedherein previous efforts to reduce the initial sodium drop insorbent-based dialysis have been by modifying the sorbent duringsynthesis, or by infusion of salt solution to the regenerated dialysate.The sorbent comprises an ion exchange system which converts urea toammonium ions, and which is configured to exchange ammonium ions forpredominantly hydrogen ions and to exchange essential cations forpredominantly sodium ions. This may comprise uremic toxin-treatingenzyme particles, which may be intermixed with cation exchange particlesas well as with anion exchange particles.

A combination of cation exchange material and anion exchange material isselected for properties, which favour ammonium to proton exchange, whileessential cation to sodium exchange is unaffected. Therefore the sodiumconcentration in regenerated dialysate is independent of the ammonium(i.e. urea) concentration in spent dialysate. Rather, the absoluteamount of sodium in regenerated dialysate is dependent on the sodiumreleased in exchange for cations such as calcium, magnesium andpotassium in spent dialysate, which are known to be subject tocomparatively small (absolute) concentration fluctuations. In fact, theconcentration of Ca, Mg and K is approximately equal to theconcentration predetermined by the dialysate regeneration andreconstitution process in the dialysis system. The present inventionthus also relates to using a sorbent as described above, in conjunctionwith an infusion (reconstitution) system configured to compensate the(approximately constant) sodium release originating from exchange of Ca,Mg and K during dialysate regeneration. The sorbent preferentiallycomprises a sufficient amount of soluble sodium salt to prevent aninitial “sodium drop” in regenerated dialysate. Reconstitution, i.e.infusion of Ca, Mg and K ions is then done with a solution which is setto a concentration which matches the concentration of released sodium,thus resulting in a desired target sodium concentration afterreconstitution. In practice, the infusate solution is provided at atotal cation concentration which is approximately equal to the targetsodium concentration.

Thus the present invention allows for a process for regeneratingdialysate in which a predetermined amount of cations such as Ca²⁺, Mg²⁺and K⁺ is added to replenish dialysate from which metabolic wasteproducts have been removed through contact with the sorbent as justdescribed. The regenerated and reconstituted dialysate is reinfused to apatient in need of such treatment. Following dialysis, the spentdialysate will contain a known amount of the cations and will thereforerelease a corresponding amount of sodium ions from the sorbent; hencethe sodium ion concentration is determined by the concentration ofcations previously added to reconstitute regenerated dialysate. Theresult is an unprecedented exact control over the sodium concentrationin regenerated and reconstituted dialysate, without the need foradditional (feedback-controlled) re-infusion systems.

The above described ion exchange behaviour would previously not havebeen considered desirable, as it requires a comparatively low“pre-loading” of ion exchange material with sodium ions. Without thehere described addition of a soluble sodium salt within the sorbentsystem, this would lead to a pronounced “sodium drop” in the early phaseof sorbent-based dialysis treatment, with potentially harmful exposureof the patient to low concentrations of sodium, low pH and consequentlylow bicarbonate concentrations. Furthermore, without the addition of asoluble sodium salt, such an exchange system would likely result in astrongly negative total sodium balance, where excessive amounts ofsodium would be removed from the patient in the early phase of atreatment, without being replenished in the later phase of thetreatment.

To overcome these complications, the sorbent is combined with a solublesource of sodium ions, such as a soluble sodium salt, which may beintermixed with at least one component of the sorbent material. Incontrast to previously described sorbents, this combination provides theunique advantages of differential exchange behaviour, while concurrentlyallowing the maintenance of physiological conditions necessary for asafe and effective dialysis treatment. The inclusion of a soluble sodiumsalt intermixed with sorbent materials also provides unique advantagesover alternative approaches such as e.g. the use of a strongly basicanion exchange material intermixed with an acidic cation exchangematerial, or the use of sodium releasing anion exchange materials suchas sodium zirconium carbonate, as these materials are characterised bypartial exchange of ammonium to sodium, and thus increased release ofsodium, and dependence of spent dialysate urea concentration, bothcontrasting with the here described sorbent properties of selectiveexchange behaviour for ammonium and Ca/Mg and K.

Furthermore, it would previously have been considered undesirable toprovide a sorbent as described here, which is characterised by aregeneration process which continuously releases sodium, while entirelyavoiding a phase of initial “sodium drop”. In a conventional sorbentsystem, this situation would have been expected to lead to an excessiveincrease of dialysate sodium concentration, resulting in excessiverelease of sodium to the patient, and thus to a potentially harmfulsituation for the patient. This is efficiently prevented and controlled,by using a sorbent which exclusively releases sodium in exchange for Ca,Mg and K, by preventing a “sodium drop” through addition of a solublesodium source, and by configuration of the reconstitution to use aninfusate which has a concentration that matches the target dialysatesodium concentration.

The term “sorbent” as used herein broadly refers to a class of materialscharacterized by their ability to absorb the desired matter of interest.

The term “metabolic wastes” in the context of this specification, meansany constituents, typically toxic constituents, within a dialysate thatare produced by metabolism and which are desirable to be removed in adialysate detoxification process. Typical metabolic wastes include, butare not limited to phosphates, urea, creatinine and uric acid.

The term “essential cations” as used herein refers to cations other thansodium ions that are present in dialysis solutions and are essential fortheir safe and effective use. These ions are generally calcium andmagnesium ions but potassium ions may also be present. Calcium,magnesium and potassium are removed by the sorbent and need to bereintroduced to regenerated dialysate to reconstitute the dialysate.

The term “cation equivalents” or “total cation equivalents” refers tothe sum of all positive charge equivalents, except protons in asolution. It is measured in mEq/L.

The term “sodium” or the symbol “Na” may be used in the specification torefer to sodium ions rather than to the element itself, as would be wellunderstood by the person skilled in the art. Accordingly, the terms“sodium”, “Na”, “sodium ions” and “Na⁺” are used interchangeably.Likewise, the terms “calcium”, “magnesium” and “potassium” or thesymbols “Ca”, “Mg” and “K” may be used in the specification to refer tocalcium ions, magnesium ions and potassium ions, respectively.

The term a “source of spent dialysate” as used herein is a reference toa source of dialysate however it is produced. The source may be anysource of spent fluid where the regeneration of biological fluids takesplace by exchange across a membrane. If, for example, the dialysisprocess is haemodialysis then the source of the spent dialysate will bea dialyser in a haemodialysis apparatus. In such apparatus streams ofblood from a patient and dialysate are in counter-current flow, andexchange takes place across a membrane separating the streams.Alternatively it may be a patient as, for example, in peritonealdialysis where dialysate is introduced to a patient's peritoneal cavityfor exchange to take place.

The term “cation exchange particles” as used herein refers to particlescapable of capturing or immobilizing cationic or positively chargedspecies when contacted with such species, typically by passing asolution of the positively charged species over the surface of theparticles.

The term “anion exchange particles” as used herein refers to particlescapable of capturing or immobilizing anionic or negatively chargedspecies when contacted with such species, typically by passing asolution of the negatively charged species over the surface of theparticles.

The term “uremic toxin-treating enzyme” as used herein refers to anenzyme able to react with a uremic toxin as a substrate. For example,the uremic toxic-treating enzyme may be an enzyme able to react withurea as a substrate, with uric acid as a substrate, or with creatinineas a substrate. Uremic enzymes can be determined to have this functionin vitro, for example, by allowing the enzyme to react with a uremictoxin in solution and measuring a decrease in the concentration of theuremic toxin. Examples of uremic toxin-treating enzymes include, but arenot limited to, ureases (which react with urea), uricases (which reactwith uric acid), or creatininases (which react with creatinine).

The term “uremic toxin” as used herein refers to one or more compoundscomprising waste products, for example, from the breakdown of proteins,nucleic acids, or the like, as would be well understood by the personskilled in the art. Non-limiting examples of uremic toxins include urea,uric acid, creatinine, and beta-2 (β₂) microglobulin. In healthyindividuals, uremic toxins are usually excreted from the body throughthe urine. However, in certain individuals, uremic toxins are notremoved from the body at a sufficiently fast rate, leading to uremictoxicity, i.e. a disease or condition characterized by elevated levelsof at least one uremic toxin with respect to physiologically normallevels of the uremic toxin. Non-limiting examples of disordersassociated with uremic toxins include renal disease or dysfunction,gout, and uremic toxicity in subjects receiving chemotherapy.

The term “uremic toxin-treating enzyme particles” as used herein refersto a uremic toxin-treating enzyme in particle form. The enzymes may beimmobilized by way of a covalent or physical bond to a biocompatiblesolid support, or by cross-linking, or encapsulation, or any othermeans.

The term “soluble source” as used herein refers to a compound distinctfrom other components of the sorbent which may be added to and mixedwith the other components, or be present as a separate layer or in acompartment separate from other sorbent components. It will usually beadded to the sorbent in the form of solid particles which intermix withother solid particles in the sorbent.

The term “biocompatible” as used herein refers to the property of amaterial that does not cause adverse biological reactions to the humanor animal body.

The term “homogeneous” as used herein refers to a substantiallyhomogeneous mixture, meaning a mixture have the same proportions of thevarious components throughout a given sample, creating a consistentmixture. The composition of the mixture is substantially the sameoverall, although it will be appreciated that in mixing solid particlesthere may be regions in a sample where mixing is not complete.

The term “particle size” refers to the diameter or equivalent diameterof the particle. The term “average particle size” means that a majoramount of the particles will be close to the specified particle sizealthough there will be some particles above and some particles below thespecified size. The peak in the distribution of particles will have aspecified size. Thus, for example, if the average particle size is 50microns, some particles which are larger and some particles which aresmaller than 50 microns will exist.

The terms “regenerate” or “regenerated” as used herein refer to theaction of detoxifying dialysate by destruction and/or absorption ofuremic toxins by a sorbent.

The term “regenerated dialysate” as used herein refers to dialysatewhich has been detoxified by destruction and/or absorption of uremictoxins by a sorbent.

The term “reconstitute” or “reconstituted” as used herein refer to theaction of converting regenerated dialysate to essentially the same stateand chemical composition as fresh dialysate prior to dialysis.

The term “reconstituted dialysate” as used herein refers dialysate whichhas been converted to essentially the same state and chemicalcomposition as fresh dialysate prior to dialysis.

The term “predominantly” as used herein is intended to represent asituation or state which occurs for the most part or principally, whilenot excluding the possibility that some amount of another situation orstate also occurs to a minimal extent. For example, it may be >80%or >90% or >95% or greater than 99%. For the avoidance of doubt, thepossibility that only that situation or state occurs, to the exclusionof all others, is covered by the term.

The word “substantially” does not exclude “completely” e.g. acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

Unless specified otherwise, the terms “comprising” and “comprise”, andgrammatical variants thereof, are intended to represent “open” or“inclusive” language such that they include recited elements but alsopermit inclusion of additional, unrecited elements. The terms may alsobe given an exclusive meaning equivalent to the term “consisting of”where the context requires this.

As used herein, the term “about”, in the context of concentrations ofcomponents of the formulations, typically means ±5% of the stated value,more typically +/−4% of the stated value, more typically ±3% of thestated value, more typically, +/−2% of the stated value, even moretypically ±1% of the stated value, and even more typically +/−0.5% ofthe stated value.

Throughout this disclosure, certain embodiments may be disclosed in arange format. It should be understood that the description in rangeformat is merely for convenience and brevity and should not be construedas an inflexible limitation on the scope of the disclosed ranges.Accordingly, the description of a range should be considered to havespecifically disclosed all the possible sub-ranges as well as individualnumerical values within that range. For example, description of a rangesuch as from 1 to 6 should be considered to have specifically disclosedsub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4,from 2 to 6, from 3 to 6 etc., as well as individual numbers within thatrange, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of thebreadth of the range.

The uremic toxin-treating enzyme may be immobilized on any known supportmaterial, which can provide immobilization for the uremic toxin-treatingenzyme particles. Immobilization may be by physical means such as byadsorption on alumina. In an embodiment non-immobilised enzyme is used.Alternatively, other methods are used to convert urea to ammonia.

In one embodiment, the support material is a biocompatible substrate towhich the enzyme is covalently bound. The biocompatible material may bea carbohydrate-based polymer, an organic polymer, a polyamide, apolyester, or an inorganic polymeric material. The biocompatiblesubstrate may be a homogeneous substrate made up of one material or acomposite substrate made up of at least two materials. The biocompatiblesubstrate may be at least one of cellulose, Eupergit, silicon dioxide(e.g. silica gel), zirconium phosphate, zirconium oxide, nylon,polycaprolactone and chitosan.

In one embodiment, the immobilization of the uremic toxin-treatingenzyme on the biocompatible substrate is carried out by immobilizationtechniques selected from the group consisting of glutaric aldehydeactivation, activation with epoxy groups, epichlorohydrin activation,bromoacetic acid activation, cyanogen bromide activation, thiolactivation, and N-hydroxysuccinimide and diimide amide coupling. Theimmobilization techniques used may also involve the use of silane-basedlinkers such as (3-aminopropyl) triethoxysilane, (3-glycidyloxypropyl)trimethoxysilane or (3-mercaptopropyl) trimethoxysilane. The surface ofthe biocompatible substrate may be further functionalized with areactive and/or stabilizing layer such as dextran or polyethyleneglycol,and with suitable linker- and stabilizer molecules such asethylenediamine, 1,6-diaminohexane, thioglycerol, mercaptoethanol andtrehalose. The uremic toxin-treating enzyme can be used in purifiedform, or in the form of crude extract such as extract of urease fromJack Bean or other suitable urease sources.

The uremic toxin-treating enzyme particles may be capable of convertingurea to ammonium carbonate. In one embodiment the uremic toxin-treatingenzyme is at least one of urease, uricase and creatininase. In apreferred embodiment, the uremic toxin-treating enzyme is urease.

In one embodiment, the uremic toxin-treating enzyme particles are ureaseparticles.

In one embodiment the uremic toxin-treating enzyme particles have anaverage particle size in the range of from about 10 microns to about1000 microns, about 100 microns to about 900 microns, about 200 micronsto about 900 microns, about 300 microns to about 800 microns, about 400microns to about 700, 500 microns to about 600 microns, about 25 micronsto about 250 microns, about 25 microns to about 100 microns, about 250microns to about 500 microns, about 250 microns to about 1000 microns,about 125 microns to about 200 microns, about 150 microns to about 200microns, about 100 microns to about 175 microns, and about 100 micronsto about 150 microns.

In one embodiment, 1000 to 10000 units of urease are immobilized on saidbiocompatible substrate. The overall weight of immobilized urease andthe substrate ranges from about 0.5 g to about 30 g.

In one embodiment, the cation exchange particles comprise an amorphous,water-insoluble metal phosphate in protonated form. In one embodimentthe metal is selected from the group consisting of titanium, zirconium,hafnium and combinations thereof. In one embodiment, the metal whosephosphate is poorly soluble in water is zirconium. Poorly solublephosphates are to be understood here as phosphates having a solubilitynot higher than 10 mg/L in water. Preferably, the cation exchangeparticles are zirconium phosphate particles which are configured toexchange ammonium ions for predominantly hydrogen ions and to exchangeessential cations for sodium ions.

In an embodiment the cation exchange particles are configured toexchange ammonium ions for predominantly hydrogen ions and to exchangeessential cations for sodium ions by setting them to low pH duringsynthesis. To optimise this property, the cation exchange particles aretypically set to low pH and low sodium loading during synthesis. In anembodiment the cation exchanger is synthesised in the presence of anacid. The pH is set by adjustment to a desired level, such as bytitration with a base such as sodium hydroxide to raise the pH to alevel which provides the desired differential exchange behaviour. Thetitration also serves to provide the cation exchange particles with asufficient loading of sodium to enable the desired exchange of sodiumfor calcium, magnesium and potassium. In an embodiment the cationexchange material is zirconium phosphate. This may be synthesised inconventional processes such, for example, from Basic Zirconium Sulfate(BZS) or from zirconium carbonate by reaction with phosphoric acid. Ifother acids are used a source of the phosphate group must be provided.Typically the pH is set to be in the range of 3.5 to 5.0, advantageouslyabout 4.5, by titration of the reaction product with a base.

The zirconium phosphate particles may have an average particle size inthe range of from about 10 microns to about 1000 microns, about 100microns to about 900 microns, about 200 microns to about 900 microns,about 300 microns to about 800 microns, about 400 microns to about 700,500 microns to about 600 microns, about 25 microns to about 200 micronsor from about 25 microns to about 150 microns or from about 25 micronsto about 80 microns or from about 25 microns to about 50 microns or fromabout 50 microns to about 100 microns or from about 125 microns to about200 microns, or from about 150 microns to about 200 microns, or fromabout 100 microns to about 175 microns, or from about 100 microns toabout 150 microns or from about 150 microns to about 500 microns, orfrom about 250 microns to about 1000 microns. The zirconium phosphateparticles may be immobilized on any known support material, which canprovide immobilization for the zirconium phosphate particles. In oneembodiment, the support material is a biocompatible substrate. In oneembodiment, the immobilization of the zirconium phosphate particles is aphysical compaction of the particles into a predetermined volume. In oneembodiment, the immobilization of the zirconium phosphate particles isachieved by sintering zirconium phosphate, or a mixture of zirconiumphosphate and a suitable ceramic material. The biocompatible substratemay be a homogeneous substrate made up of one material or a compositesubstrate made up of at least two materials

Suitable cation exchange materials are materials which are configured toexchange ammonium ions for predominantly hydrogen ions and to exchangeessential cations for sodium ions. This property may be determined bymeasuring the ion exchange capabilities of the material. Measuring thechange in sodium ion concentration over time in the presence of calcium,magnesium and/or potassium ions ought to result in an increase in sodiumion concentration but there will be no change in the absence of calcium,magnesium and/or potassium ions even if ammonium ions generated by thebreakdown of urea are present.

The anion exchange particles may comprise of an amorphous and partlyhydrated, water-insoluble metal oxide in its hydroxide-, carbonate-,acetate-, and/or lactate-counter-ion form, wherein the metal may beselected from the group consisting of titanium, zirconium, hafnium andcombinations thereof. In one embodiment, the metal is zirconium. Theanion exchange particles may be zirconium oxide particles. Preferably,the anion exchange particles are hydrous zirconium oxide particles.

In an embodiment the anion exchange particles are set to an alkaline pH.In an embodiment they are set to a pH in the range of from 7 to 14. Inan embodiment they are set to a pH of from 12 to 13. One way to achievethis is to saturate the anion exchange particles with a base. In anembodiment the base is selected from the group consisting of sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,magnesium hydroxide;

calcium hydroxide, calcium carbonate, magnesium carbonate, potassiumcarbonate, potassium bicarbonate, ammonium carbonate and ammoniumhydroxide. Preferably the base is selected from the group consisting ofsodium hydroxide, sodium carbonate and sodium bicarbonate. Alkalineanion exchange particles are preferred to produce the desired selectivesorbent exchange properties for ammonium and Ca/Mg/K, respectively,particularly when combined with acidic cation exchange particles asdescribed above. It will be appreciated that the metal oxides used asanion exchange materials are typically synthesised by converting aprecursor such as a carbonate to the oxide by reaction with hydroxide,followed by an optional titration, and that not washing the product willretain excess hydroxide within the product. If a sodium salt is usedthen the base can act as the source of sodium ions, hence sodiumhydroxide is preferred if unwashed anion exchange particles are used.

The zirconium oxide particles may have an average particle size in therange of from about 10 microns to about 1000 microns, about 100 micronsto about 900 microns, about 200 microns to about 900 microns, about 300microns to about 800 microns, about 400 microns to about 700, 500microns to about 600 microns, about 10 microns to about 200 microns orfrom about 10 microns to about 100 microns or from about 10 microns toabout 30 microns or from about 10 microns to about 20 microns or fromabout 20 microns to about 50 microns or from about 25 microns to about50 microns or from about 30 microns to about 50 microns or from about 40microns to about 150 microns or from about 80 microns to about 120microns or from about 160 microns to about 180 or from about 25 micronsto about 250 or from about 250 microns to about 500 or from about 250microns to about 1000. The zirconium oxide particles may be immobilizedon any known support material which can provide immobilization for thezirconium oxide particles. In one embodiment, the immobilization of thezirconium phosphate particles is a physical compaction of the particlesinto a predetermined volume. In one embodiment, the immobilization ofthe zirconium oxide particles is achieved by sintering zirconium oxide,or a mixture of zirconium oxide and a suitable ceramic material. In oneembodiment, the support material is a biocompatible substrate. Thebiocompatible material may be a carbohydrate-based polymer, an organicpolymer, a polyamide, a polyester, a polyacrylate, a polyether, apolyolefin or an inorganic polymeric or ceramic material. Thebiocompatible substrate may be at least one of cellulose, Eupergit,silicon dioxide, nylon, polycaprolactone and chitosan.

In one embodiment, the zirconium oxide particles may be replaced by anyparticles that are able to absorb phosphate ions and other anions.Preferably, the particles are able to absorb anions selected from thegroup comprising ions of phosphate, fluoride, nitrate and sulphate. Thezirconium oxide particles may also release ions such as acetate,lactate, bicarbonate and hydroxide in exchange for the anions absorbed.In one embodiment, the zirconium oxide particles are also good bindersfor iron, aluminium and heavy metals selected from the group consistingof arsenic, bismuth, cadmium, cobalt, copper, lead, mercury, nickel,palladium and silver.

In an embodiment the ratio of cation exchange particle to anion exchangeparticle is in the range of 1:1 to 5:1. In an embodiment the ratio ofcation exchange particle to anion exchange particle is in the range of2:1 to 3:1. In an embodiment the ratio of cation exchange particle toanion exchange particle is about 2.4:1. The anion exchanger acts as a pHbuffer for the low pH cation exchanger however, at this ratio, thebuffer capacity of anion exchanger particles alone is insufficient tocompensate for the acidification and the drop in sodium concentration bythe cation exchanger.

The sorbent comprises a soluble source of sodium. The provision ofsodium overcomes the initial drop in sodium concentration. Accordingly asorbent material in accordance with the present invention will exhibit alesser drop in sodium ion concentration compared to conventionalmaterials in an initial phase of a dialysis process. Ideally there willbe no initial drop in sodium ion concentration.

In an embodiment the soluble source of sodium ions may be particles of asoluble salt. In an embodiment the soluble salt is a basic salt. In anembodiment the soluble salt is selected from one or more of the groupconsisting of sodium carbonate, sodium bicarbonate and sodium hydroxide.It may also be a neutral salt, such as sodium chloride, or a salt of aweak acid such as e.g. sodium lactate or sodium acetate.

The production of the desired exchange selectivity requires acomparatively low Na-loading of the sorbent materials during synthesis.Therefore it is necessary to add a separate source of sodium ions toovercome the initial Na-drop caused by the sorbent material.

The sorbent comprises bicarbonate which is both generated in thebreakdown of urea and carried from the patient in the dialysate. Thereis an initial drop in bicarbonate concentration due to neutralisationwith hydrogen ions released from the cation exchanger, which results information of carbon dioxide. Carbonate and/or bicarbonate may beintroduced by adding a salt directly to the sorbent to compensate. Thiscould be done by introducing, for example, sodium carbonate, sodiumbicarbonate, or by introducing weak acid salts such as sodium acetate orsodium lactate which result in an increased bicarbonate in thedialysate. The sodium salt is preferred since it may also act as asource of sodium. There also needs to be a pH balance achieved since theamount of anion exchanger is insufficient to compensate for the low pHcation exchanger. The balance may be achieved by the introduction of abasic material such as e.g. sodium hydroxide, sodium carbonate or sodiumbicarbonate While such compounds could be added separately to addresseach of the drops, it will be appreciated that the introduction ofsodium carbonate or sodium bicarbonate addresses all deficiencies; hencesodium carbonate and sodium bicarbonate are the preferred source ofsodium ions.

While not wishing to be bound by theory, it is believed that the sorbentpredominantly converts urea to CO₂, allowing for the chemistry ofsorbent-based dialysate regeneration to be largely independent of theurea concentration in the spent dialysate. In a first step, ureacontained in spent dialysate is converted to ammonium and bicarbonate.In a second step, the ion exchanger exchanges ammonium predominantlywith protons. The protons then recombine with bicarbonate to form CO₂,which is released from the system. Cations such as calcium, magnesiumand potassium are predominantly exchanged with sodium. Advantageouslythe sorbent is a homogeneous mixture containing a calculated amount ofsodium carbonate and/or sodium bicarbonate. The addition of sodiumcarbonate/sodium bicarbonate influences the sodium concentration inregenerated dialysate, without changing the sorbent's exchangecharacteristics.

The sorbent may optionally contain carbonic anhydrase to facilitate theCO₂ release. Carbonic anhydrase catalyses a reaction in which carbondioxide and water are converted to carbonic acid, protons andbicarbonate ions. By way of example, carbonic anhydrase from human orbovine erythrocytes and recombinant human carbonic anhydrase may beused. Carbonic anhydrase may be immobilized on any known supportmaterial, as described previously for the uremic toxin-treating enzymeparticles. Carbonic anhydrase may be immobilized separately to theuremic toxin-treating enzyme particles or to the same particles.

In one embodiment the sorbent further comprises an organic compoundsabsorber. The organic compounds absorber may be intermixed with theuremic toxin-treating enzyme particles and cation exchange particlesand/or anion exchange particles, or may form a separate layer. Theorganic compounds absorber may be selected from the group consisting,amongst others, of activated carbons, molecular sieves, zeolites anddiatomaceous earth. The organic compounds absorber particles may beactivated carbon particles. In one embodiment, the organic compoundabsorber in the primary layer is an activated carbon filter pad. Inanother embodiment, the organic compound absorber comprises activatedcarbon particles.

The activated carbon particles may have an average particle size in therange of from about 10 microns to about 1000 microns, about 10 micronsto about 250 microns, about 20 microns to about 200 microns, about 25microns to about 150 microns, about 50 microns to about 100 microns,about 25 microns to about 250 microns or from about 100 microns to about200 microns or from about 100 microns to about 150 microns or from about150 microns to about 300 microns or from about 200 microns to about 300microns or from about 400 microns to about 900 microns or from about 500microns to about 800 microns or from about 600 microns to about 700microns or from about 250 microns to about 500 microns or from about 250microns to about 1000 microns.

In one embodiment, the activated carbon particles may be replaced by anyparticles that are able to absorb organic compounds. Preferably, theparticles are able to absorb organic compounds and/or organicmetabolites selected from the group comprising creatinine, uric acid andother small and medium sized organic molecules without releasinganything in exchange. The activated carbon particles may also bephysically compacted into a predetermined volume for the purpose ofspace economy. In one embodiment, the activated carbon particles arephysically compacted into an activated carbon filter pad.

The invention also provides a process of preparing a sorbent comprisingmixing immobilized uremic toxin-treating enzyme particles which converturea to ammonium ions with cation exchange particles, configured toexchange ammonium ions for predominantly hydrogen ions and to exchangeessential cations for sodium ions, and further comprising providing asodium source, and optionally mixing anion exchange particles and/ororganic compounds absorber particles.

In one embodiment, the sorbent is housed in at least one cartridge. Thesorbent cartridges may be configured such that they are easily removablefrom the dialysis device. The sorbent cartridge may also be compact andmade of a material that is resistant to wear and tear. The cartridge maybe made from resilient, chemically and biologically inert materials. Thecartridge may also be able to withstand the pressure within the flowsystem of the dialysis device without leakage. The cartridge may be madefrom material which can withstand sterilization conditions such as heatsterilization, ethylene oxide sterilization and sterilization withionizing radiation. In one embodiment, the sorbent cartridges are madeof acrylonitrile butadiene styrene. The sorbent cartridges may also bemade of polycarbonate, polypropylene or polyethylene. In one embodiment,filter pads and filter papers may also be located at the in- and outletof the sorbent cartridges and/or between the individual layers withinthe sorbent, to filter off any particles arising from the layers of thesorbent.

The invention also relates to a process for regenerating dialysate inwhich a predetermined amount of cations such as Ca²⁺, Mg²⁺ and K⁺ isadded to replenish dialysate from which metabolic waste products havebeen removed through contact with the sorbent of the present invention.Following dialysis, the spent dialysate will contain a known amount ofthe cations and will therefore release a corresponding amount of sodiumions from the sorbent; hence the sodium ion concentration in regenerateddialysate is determined by the amount of cations previously added toreconstitute the dialysate. The system uses a sorbent, whichpredominantly converts urea to CO₂, and predominantly exchanges cationssuch as calcium, magnesium and potassium to sodium. The concentration ofthe infusate is chosen such that the amount of sodium exchanged for theconstituents of the infusate (Ca, Mg, K) results in a desired targetsodium concentration, when recombined with the infusate volume used forreconstitution with Ca, Mg and K. Thus the system for dialysateregeneration and reconstitution comprises an intrinsically regulatedinfusion system. The system can produce specific sodium profiles, ormaintain constant sodium concentration in regenerated dialysate withoutthe need for a feedback control system.

One advantages of this invention is the ability to maintain sodiumlevels in the dialysis solution within a desired range. This can help toreduce discomfort experienced by the patient as a result of increased ordecreased sodium levels in the patient's blood.

The system of this invention is able to control the dialysate sodiumconcentration with significantly smaller variations than conventionaldialysis apparatus. For example, accuracies of ±5% of a targetconcentration are achievable. For example the system can maintaindialysate sodium concentrations within a range from 132 to 145 mEq/L.Further, specific concentration profiles are accessible, e.g. for“sodium modelling”, and can equally be achieved with ±5% accuracy.Bicarbonate and chloride concentrations are significantly bettercontrolled than in prior art.

The sorbent system of this invention allows the use of chloride saltsfor electrolyte re-infusion, whereas previous systems had to use saltsof a weak acid, such as acetate salts in order to keep dialysate buffersystem (buffer concentration and CI concentration) within physiologicalrange. Acetate salts are more costly, and more troublesome to beprovided in a sterile and stable form (changes of composition duringsterilisation and storage) than chloride salts. However, while thepresent invention allows the possibility to provide infusate solutionsbased on chloride salts of Ca, Mg and K, the system is not limited tothese salts. Chloride salts may partially be replaced by lactate salts,without changing the total salt concentration or the infusion ratio. Asthere would only be a partial replacement of chloride by lactate, theresulting infusate solution would not be limited by solubility issues.Advantageously, such mixed salt solutions may be used to increase thebuffer capacity of a regenerated dialysate, countering a patient'sacidosis. More advantageously, such solutions may be similar tocommercially available solutions for parenteral infusion, and may besuitable for steam sterilisation.

The resulting system is simple, robust, small, cost efficient, and has asmaller number of components as compared to prior art. While not wishingto be bound by theory, it is believed that this is due to thecharacteristic of the sorbent to exchange ammonium predominantly toprotons, while bivalent cations and potassium are predominantlyexchanged to sodium. This is a result of the sorbent ion exchange design(zirconium phosphate), which is deliberately set to lower pH and lowersodium loading during sorbent synthesis. Surprisingly, it was found thatthe cation exchange properties for calcium, magnesium and potassium areindependent of the sorbent pH, while the ammonium exchange property isstrongly dependent on the pH. This allows one to produce an ion exchangematerial with a pH that favours ammonium to proton exchange, while forcalcium, magnesium and potassium to sodium exchange is unaffected. Thesorbent of the current invention combines such optimized zirconiumphosphate with alkaline pH hydrous zirconium oxide in order to maintainthe pH of regenerated dialysate within a desired target range, e.g. from6.0 to 8.0, while not interfering with ion exchange selectivity. Thissystem is subject to a marked Na-drop to a dialysate Na-concentration ofapprox. 100 mEq/L in the early phase of dialysis. To counter thisNa-drop, a calculated amount of sodium bicarbonate, sodium carbonate,sodium chloride or sodium hydroxide is added to the homogeneous sorbentmixture. In consequence, the sodium concentration in regenerateddialysate is independent of the ammonium (i.e. urea) concentration inspent dialysate. Rather, the absolute amount of sodium exchange isdependent on the concentrations of calcium, magnesium and potassium inspent dialysate, which are known and subject to only minor fluctuations.These concentrations are in fact determined by the dialysateregeneration and reconstitution process in the dialysis system. Forexample, typical K, Ca and Mg concentrations are 2, 3 and 1 mEq/L. Thatis, the actual amount of sodium released during the regeneration processis known, and is directly dependent of the K, Ca, and Mg concentrationsdetermined by the system during the regeneration process. This allowscalculation of the concentration of the solution used to administer K,Ca and Mg such that the volume increase through infusion of thisconcentrate accurately matches the sodium increase caused by the ionexchange of K, Ca, and Mg. For example, the concentration of the K, Ca,and Mg solution can be set such that the equivalents of sodium releasedin return for the combined equivalents of K, Ca and Mg are met by therequired volume of solution to produce a desired target Na concentrationof e.g. 138 mEq/L. For example, the regeneration of 1L of spentdialysate containing 3 mEq/L of K, 3 mEq/L of Ca and 1 mEq/L of Mg mayresult in a total release of 5 to 7 mEq, e.g. 7 mEq of sodium. Thesystem of the current invention advantageously administers a concentratesolution to reconstitute K, Ca and Mg, which has a total volume of 51 mLto reconstitute said 1L of spent dialysate. 7 mEq of sodium increasethus meet with 51 mL of volume increase, which results formally in asodium concentration of 7/0.051 mEq/L=138 mEq/L in the added fluidcomponents. Crucially, this concentration is the same as the targetconcentration and thus does not affect the sodium concentration in thetotal regenerated volume of 1.051L. Based on this model, the preferredmixing ratio of regenerated dialysate and K, Ca and Mg concentrate is1000:51. It should be noted that this mixing ratio is based on anidealised calculation, which may be further fine-tuned by empiricaloptimisation. In practice the concentration of sodium ions and theessential ions is prescribed by a physician. Several configurations canbe provided, which may differ by composition of the infusate solution,or by the dose volume of infusate solution. A steady state with regardto sodium concentration may be maintained. Alternatively, other mixingratios can produce an intentional deviation from a target concentration,e.g. as in sodium modelling. Alternatively, different targetconcentrations of Ca, Mg, K and Na may be achieved using differentconcentration solutions and different infusion volume ratios.

In an embodiment the infusate concentrate solutions may further compriseosmotic agents such as glucose, to ensure correct osmotic pressure ofdialysate after infusion.

In an embodiment the infusate concentrate solutions may further compriseadditional salts such as sodium chloride, which can function as avariable component, or “placeholder” substituting other chloride saltsfor different target concentrations of Ca, Mg and K. Advantageously,this allows the provision of a series of infusate concentrates which canall be administered using the same infusion volume ratio, therebyfacilitating device design. For example, such concentrate solutions mayalso contain an intentionally low sodium chloride concentration, thusallowing the creation of a negative sodium gradient in dialysate afterinfusion.

Non-limiting examples which embody certain aspects of the invention willnow be described.

DETAILED DESCRIPTION OF DRAWINGS

Two experimental setups of different scales were used. The differenceswere as shown in Table 1.

TABLE 1 Miniature Size Full Size Total Volume Dialysate + simulatedDialysate 2 L patient blood 300 mL Infusate 4-5 L Infusate 30-140 mLSimulated patient 40 L Dialysate flow rate 9.1 mL/min 300 mL/minInfusate flow rate 0.126-0.583 mL/min 15-20 mL/min Total therapy volume2.18 L 72 L Time 4 h 4 h Total urea challenge 19 mmol 640 mmol (18 gurea-N) Total salt infusion 15 mEq 500 mEq

Components of Infusion/Toxin Solution:

-   -   Cations infusate: Ca²⁺-1.5 mmol/L, Mg²⁺-0.5 mmol/L, K⁺-3.0        mmol/L; and    -   Toxin: urea-8.9 mmol/L, creatinine-370 μmol/L and phosphate-1.3        mmol/L.

In conventional sorbent dialysis arrangements, 6 L of dialysate and upto 1 L of infusate are used. In an embodiment of the present invention,2 L of dialysate and 4 to 5 L of infusate are used. Accordingly, thetotal fluid volume required to complete the dialysis therapy isrelatively unchanged in the present invention as compared toconventional sorbent dialysis. Conventional sorbent dialysis uses alarge dialysate reservoir volume (as large as 6L for a REDY system) tobuffer changes in sodium, bicarbonate, and pH; while infusate was keptto a smaller volume (14 In the current invention, although a largerinfusate volume is used to achieve the required infusion, the dialysatereservoir is no longer required to act as a buffer volume and can bereduced to 2L:

The miniature setup 10 is as shown in FIG. 2 . The process firstinvolves drawing a sample flow from a spent dialysate reservoir 15fitted with a stirrer 20, in which the dialysate flow is heated at 37°C. by a heat exchanger 25. The flow rate is controlled by a pump 30,coupled to a pressure dampener and sensor 35. Initially, a solutioncontaining urea is introduced to the spent dialysate reservoir. Thismimics spent dialysate from a first cycle of dialysis once it is heatedby passage through the heat exchanger 25. The spent dialysate thenpasses through a sorbent cartridge 40 to produce a regenerateddialysate. The level of ammonia may be monitored by an ammonia sensor45. One suitable ammonia sensor is disclosed in WO2017/034481, thecontents of which are incorporated herein by reference. Aninfusate/toxin solution 50 is fed into the regenerated dialysate in thisexperimental system. The purpose is both to maintain the saltconcentration as described herein and to closely mimic the conditionswhen patients are treated. The experimental system adds toxins togetherwith the infusate but it will be appreciated that the infusate wouldordinarily be introduced to the regenerated dialysate before thedialysate is reused for dialysis. In peritoneal dialysis thereconstituted dialysate would be introduced to the peritoneal cavity ofthe patient for diffusion of toxins to take place, while inhaemodialysis toxins diffuse across a membrane as reconstituteddialysate flows through a dialyser in the opposite direction to thepatient's blood. In the experimental system the reconstituted dialysatecontains toxins and so is treated as spent dialysate for a second cycle.The spent dialysate is returned to the spent dialysate reservoir 15. Thespent dialysate is drawn from the spent dialysate reservoir fortreatment in the sorbent in a second cycle. A gas burette 55 measuresthe volume of carbon dioxide gas that is produced in each cycle. Asample of the spent dialysate and regenerated dialysate was collectedthrough sample ports 60 (spent dialysate) and 65 (regenerateddialysate), respectively, in each cycle for analysis. The miniaturesetup 10 was used in investigating the effect of how differentcomponents of the dialysate affect the release of Na⁺ over time.

The sorbent in the sorbent cartridge 40 varies depending upon theexperiment. In each case it includes immobilized uremic toxin-treatingenzyme particles which convert urea to ammonium ions, intermixed withcation exchange particles. The cation exchange particles are configuredto exchange ammonium ions for predominantly hydrogen ions and toexchange calcium, magnesium and potassium ions for sodium ions in thecurrent invention. The cation exchange material operates at a pH thatfavours ammonium to proton exchange, while bivalent cation to sodiumexchange is unaffected (FIG. 1 ). Therefore the sodium concentration inregenerated dialysate is independent of the ammonium (i.e. urea)concentration in spent dialysate.

The toxin/infusate solution 50 consisted of an aqueous solution of Ca,Mg, K salts as well as urea, creatinine and a source of phosphate. Ca,Mg, and K were typically introduced as chloride salts. In thisexperimental system, phosphate was introduced to mimic waste generation.Typically the phosphate was introduced as H₃PO₄ or KH₂PO₄. Where KH₂PO₄was used a source of phosphate, the mass of KCl was correspondinglyreduced in a 1:1 molar ratio in order to achieve the same targetconcentration of K.

The full scale setup 110 is as shown in FIG. 3 . The double-loop processresembles that of the miniature setup but further includes a secondcircuit for a simulated patient's blood. An aqueous dialysate solutionis used to simulate patient's blood. The process first involves pumpinga sample flow from a dialysate reservoir 115 via a pump 145, through aheat exchanger 125 at 37° C. to dialyser 130 where exchange withsimulated blood takes place. The simulated blood was pumped out from areservoir 170 via a pump 180, through a heat exchanger 180 at 37° C. Theheated simulated blood then passed through the dialyser 130 beforereturning to the patient reservoir 170. Simulated blood and dialysateflow to either side of a membrane (not shown) across which theyexchange. The spent dialysate is then pumped out of the dialyser 130 viaa pump 135 and into a pressure dampener gauge 140, before it is passedthrough a sorbent cartridge 145 to regenerate the dialysate. An infusatesolution 150, controlled by an infusion pump 155, is fed into theregenerated dialysate to reconstitute the dialysate. Excess fluid isoptionally removed by a drain pump 160 into a drain reservoir 165, whilethe remaining regenerated dialysate is fed into the dialysate reservoir115.

Non-limiting examples which embody certain aspects of the invention willnow be described.

EXAMPLES Example 1—Preparation of Zirconium Phosphate

Zirconium phosphate is synthesised by conventional methods, for exampleby reaction of an aqueous mixture of Basic Zirconium Sulfate andphosphoric acid as described in U.S. Pat. No. 3,850,835. Alternatively,it is synthesised from an aqueous mixture of Sodium Zirconium Carbonateand phosphoric acid as described in U.S. Pat. No. 4,256,718.

The product was titrated to a solution pH of 4.5. A 5M solution ofsodium hydroxide was added step-wise to an aqueous slurry of thezirconium phosphate until a pH of 4.5 was reached. After the titration,the zirconium phosphate was washed until the filtrate was withinacceptable limits of leachables, and air dried.

Example 2—Preparation of Hydrous Zirconium Oxide

Hydrous zirconium oxide is synthesised.by conventional methods, forexample by reaction of an aqueous mixture of sodium zirconium carbonateand sodium hydroxide as described in U.S. Pat. No 4,256,718. Aftersynthesis of hydrous zirconium oxide, the product was titrated to a pHof from 12 to 13. This was done by making an aqueous slurry of thehydrous zirconium oxide and titrating it with 5M sodium hydroxide untilthe slurry is at a pH of 12 to 13. In some instances, the hydrouszirconium oxide was then washed until the concentration of leachables inthe filtrate was within acceptable levels, and air dried. Alternatively,the was recovered directly from the slurry and not washed before beingair dried. The subjected to a washing procedure is referred to as“washed ”. The recovered directly from the titration slurry is referredto as “unwashed ”.

Example 3—Preparation of Sorbent Mixture for Miniature Cartridges

For each experiment, the sorbent cartridge consisted of the materialslisted below. Zirconium phosphate (ZP) was prepared according toexample 1. Hydrous zirconium oxide () was prepared as described inexample 2, and both washed an unwashed material were used as indicated.Immobilised urease (IU) was prepared as described in examples 1 and 2 ofWO 2011/102807, the contents of which are incorporated herein byreference. Activated carbon (AC) has a particle size of 50 to 200micron. In general, one experimental condition was changed at a time inorder to distinguish the effect of that modification on the sodiumconcentration of the regenerated dialysate. The sodium and pH set pointof the sorbent was adjusted in two ways in these experiments:

-   -   1) Use of soluble additive (Na₂CO₃, NaHCO₃), and/or    -   2) Modification of—use of un-washed and washed

In each experiment, a glass flex-column with inlet and outlet was usedas receptacle for the sorbent. The sorbent materials, immobilised ureaseand additive were weighed individually, then mixed together and drypacked into the flex-column. The sorbent bed was secured in place with aplug of cotton wool, at which point it was ready for installation intothe dialysate circuit.

Miniature Cartridge Experiments

TABLE 2 Example title Effect of Ca, Improved Na Control of Na profileEffect of urea Mg, K infusion profile after by modificationconcentration on on dialysate modification of sorbent and dialysatechemistry chemistry of sorbent infusate composition Example 4 5 6 7 FIG.4a, 6, 7, 8, 9 4b, 10, 11, 12 13, 14, 15 6a, 6b, 6c Urea level 2.23 4.478.93 0.00 8.93 8.93 8.93 8.93 8.93 8.93 mM mM mM mM mM mM mM mM mM mMCa, Mg, K Yes Yes Yes Yes No Yes Yes Yes Yes Yes ZP (g) 40 40 40 40 4040 40 40 40 40 HZO - 17 17 17 17 17 17 17 17 17 17 washed (g) AC (g) 8.88.8 8.8 8.8 8.8 8.8 8.8 8.8 8.8 8.8 IU (g) 1.0 1.0 1.0 1.0 1.0 1.0 1.01.0 1.0 1.0 Na₂CO₃ (g) 0.54 0.54 0.54 0.54 0.54 — — 0.54 2.2 2.2 NaHCO₃(g) — — — — — 0.43 0.86 — — — Infusate 30 30 30 30 30 30 30 30 30 141vol (mL)

Example 4—Effect of Urea Concentration on Dialysate Chemistry

Three identical sorbent cartridges were constructed using a compositionas given in Table 2 and tested in the recirculating miniature dialysissetup 10 described above. The three cartridges were challenged witheither low, medium or high urea concentrations in the recirculatingminiature dialysis setup 10 described above with reference to FIG. 2 ,representing a range of incoming patient urea levels. Briefly, dialysatesolutions containing low, medium and high concentrations of urea (2.2mM, 4.5 mM and 8.9 mM) were prepared for use as the initial dialysatesolution. The toxin/infusate solution 50 was prepared so as to containsufficient urea to maintain either the low, medium or high urea level aswell as the required Ca²⁺, Mg²⁺, K⁺, creatinine and phosphateconcentrations. In each of the three experiments, toxin-containingdialysate was pumped through the sorbent cartridge, where Ca²⁺, Mg²⁺,K⁺, urea, creatinine and phosphate were removed. The dialysate was thenreconstituted by addition of the toxin/infusate solution in order tomaintain the challenge concentration of urea, creatinine and phosphateand to add Ca²⁺, Mg²⁺ and K⁺. Aliquots of the dialysate were obtainedvia the sample port 60.

The following was observed:

-   -   a) Sodium: The Na⁺ concentration over time for all three urea        concentrations showed a similar trend, indicating that the        concentration of urea did not have an effect on the release of        Na⁺from the sorbent cartridge (FIG. 4 a ).    -   b) Bicarbonate: HCO₃ ⁻ profile shows only a weak dependency on        the dialysate urea concentration. There is an initial loss of        HCO₃ ⁻ in line with the described bicarbonate drop.        Subsequently, the apparent absence of a significant bicarbonate        increase indicates that approximately all NH₄ ⁺ formed from urea        is exchanged to H⁺, which combines with HCO₃ ⁻ formed from urea        and releases it as CO₂ (FIG. 7 ).    -   c) Chloride: Cl⁻ profile (slope) is independent of dialysate        urea concentration. There is a steady increase of Cl⁻ from        infusate addition (FIG. 8 ).    -   d) pH: pH profile shows only a weak dependency on dialysate urea        concentration (FIG. 9 ). Acidification through formal loss of        HCO₃ ⁻ and an increase of Cl⁻ from infusate addition is seen.

Example 5—Effect of Ca²⁺, Mg²⁺ and K⁺, infusion on dialysate chemistry

In order to distinguish the dialysate effects of urea (ammonium) removalvs Ca/Mg/K removal, two identical sorbent cartridges (refer to Table 2)were challenged with dialysates containing either urea or Ca Mg and K inthe recirculating miniature dialysis setup 10 described above withreference to FIG. 2 . As in Example 4, in each experiment, the dialysatewas pumped through the sorbent cartridge followed by the addition of aninfusate to replenish and to maintain the respective concentration ofCa²⁺, Mg²⁺, K⁺, urea, creatinine and phosphate of the dialysate (whererelevant). Aliquots of the dialysates were obtained via sample port 60.

The following was observed:

-   -   a) Sodium: In the absence of urea, the Na⁺ profile over time        resembled the typical profile which showed an initial drop with        a subsequent increase in Na⁺ concentration over time (FIG. 4 b        ). However, in the absence of Ca²⁺, Mg²⁺ and K⁺, the Na⁺        concentration showed a greater initial drop and it remained        relatively constant thereafter (at approximately 110 mmol/L)        (FIG. 4 b ). This shows that the increase in Na⁺ concentration        is caused by Ca²⁺, Mg²⁺ and K⁺, presumably via cation exchange        to displace and release the Na⁺ from the sorbent cartridge (FIG.        4 b ).    -   b) Bicarbonate, pH, Cl: The HCO₃ ⁻ profile shows only weak        dependency of presence of infusate or urea. Neither binding of        urea nor Ca/Mg has a significant effect on HCO₃ ⁻ (FIG. 10 ). It        was observed that Cl⁻ increased in presence of infusate, with an        approximately equal increase to the increase in Na⁺. There was        no Cl⁻ increase in the presence of urea without infusate but a        steady increase of Cl from infusate addition (FIG. 11 ). Thus,        infusate addition formally increases NaCl concentration.        Additionally, a very low pH in the presence of Ca/Mg and absence        of urea was observed (FIG. 12 ). Acidification through formal        loss of HCO₃ ⁻ and increase of Cl⁻ from infusate addition was        evident.

Example 6—Improved Na⁺ Profile after Modification

The dialysate effects of addition of soluble sodium salts to the sorbentwere investigated by testing two sorbent compositions (see Table 2,Example 6) with identical dialysate and infusate solutions in therecirculating miniature dialysis setup 10 described above with referenceto FIG. 2 . Apart from the increase in sodium bicarbonate, the sorbentswere identical in composition.

-   -   a) Sodium: An initial Na⁺ drop is prevented, or at least        reduced, by increasing the amount of (basic) Na⁺ salt in the        sorbent mixture. The slope of Na⁺ increase during steady phase        is not affected (FIG. 13 ). Thus, the addition of (basic) Na⁺        salt improves or avoids the initial Na⁺ drop apparent in        conventional systems without affecting sorbent ion exchange        behavior.    -   b) Bicarbonate: The usual initial HCO₃ ⁻ drop is significantly        improved by increasing the amount of (basic) Na⁺ salt in the        sorbent mix. The HCO₃ ⁻ increase during steady phase is not        affected, and remains at approx. zero (FIG. 13 ). Thus, the        addition of a (basic) Na⁺ salt reduces the initial HCO₃ ⁻ drop        without affecting sorbent ion exchange behavior.    -   c) Chloride: The Cl⁻ profile is essentially independent of the        amount of (basic) Na-salt in the sorbent mixture (FIG. 15 ).        Thus, the addition of a (basic) Na⁺ salt does not significantly        affect the Cl⁻ concentration.

Example 7—Modification to Sorbent and Infusate Composition to allowControl of Na⁺ Profile

In order to advantageously utilize the concepts unveiled in Examples 4,5 and 6 to build an intrinsically regulated sorbent dialysis system, aseries of experiments were conducted with modified sorbent and infusatecompositions. Three sorbent cartridges were tested in the recirculatingminiature dialysis setup 10 described above with reference to FIG. 2(see Table 2, Example 7). In the first experiment, an unmodified sorbentwas used in a simulated dialysis session with unmodified infusatesolution (FIG. 6 a ), giving the characteristic drop in sodium followedby steady increase. In the second experiment, the sorbent was modifiedto include additional Na₂CO₃ as soluble sodium salt. This corrected thedrop in sodium, but the subsequent sodium gradient remained (FIG. 6 b ).In the third experiment, the same modified sorbent was included in thedialysis circuit with a modified infusate, whereby the infusatecomposition was changed to counterbalance the dialysate sodium gradient(FIG. 6 c ). The infusate composition was amended by increasing theinfusate volume. With further modifications, it is possible to achieve anegative sodium gradient similar to sodium gradients typically appliedin sodium modelling (FIG. 6 d ). For instance, using a pre-dialysisstarting bath of Na 142 mM and performing dialysis in combination with asuitably modified infusate composition and infusion rate can producesuch a result with the sorbent disclosed herein.

Example 8—Comparative Effect of Modification, Soluble Sodium Salt andInfusion Conditions on Cation Exchange Efficiency

TABLE 3 Example 8B (repeat 8A of 8A) 8C 8D 8E 8F 8G Urea level 8.93 mM8.93 mM 8.93 mM 8.93 mM 0.00 mM 8.93 mM 8.93 mM Ca, Mg, K Yes Yes Yes NoYes Yes Yes ZP (g) 40 40 40 40 40 40 40 HZO - washed (g) 17 17 17 17 17— — HZO - unwashed (g) — — — — — 17 17 AC (g) 8.8 8.8 8.8 8.8 8.8 8.88.8 IU (g) 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Na₂CO₃ (g) — — — — — 0.54 0NaHCO₃ (g) 0.43 0.43 0.86 0.43 0.43 — 0.43 Infusate vol (mL) 30 30 30 3030 30 30 Phos source KH₂PO₄ KH₂PO₄ KH₂PO₄ H₃PO₄ KH₂PO₄ KH₂PO₄ KH₂PO₄ NH₄⁺ → H⁺ 94% 96% 94% 94 N/A 88% 90% NH₄ ⁺ → Na⁺  6%  4%  6% 6% N/A 12% 10%Ca²⁺/Mg²⁺/K⁺ → 94% 90% 85% N/A 83% 94% 94% Na+

Use of unwashed HZO (with high Na-loading) in example 8F-8G (Table 3)appeared to result in less favourable ammonium to H⁺ exchange properties(only 88% of ammonium exchanged for H⁺) as compared to use of washed HZOwith lower Na-loading (at least 94% exchange of ammonium for H⁺) inexample 8A-8E (Table 3). This suggests that the traditional approach ofsorbent modification in terms of pre-loading of ZP or HZO with Naproduces results that are inferior to use of additive as in the presentinvention.

Example 9 Formulas to Calculate Infusate Composition and Infusion Ratiofor Reconstitution Process

Solution to Maintain Stable Na Concentration:

-   -   The regenerated dialysate leaving the sorbent cartridge must be        reconstituted with a solution of Ca²⁺/Mg²⁺/K⁺ containing        approximately 138 mEq/L of combined Ca²⁺/Mg²⁺/K⁺.    -   In that way, the additional Na⁺ exchanged for Ca²⁺/Mg²⁺/K⁺ will        be met with a volume of infusate, which will reconstitute the        additional Na⁺ to a concentration of 138 mEq/L.    -   In an idealised analysis, the infusate salt concentration has to        fulfill the following condition

C^(I) _(CaMgK) +c ^(I) _(Na) =c ^(D) _(Na)

-   -   where    -   C^(I) _(CaMgK) infusate concentration of combined Ca²⁺/Mg²⁺/K⁺    -   c^(D) _(Na): target dialysate Na⁺ concentration    -   c^(I) _(Na): concentration of Na in infusate solution (if        present)

More Detailed Analysis:

In a more detailed analysis, the infusate salt concentration mustfulfill the following condition

c ^(I) _(caMgK)×η_(CaMgK) +c ^(D) _(urea)×η_(urea) +c ^(I) _(Na) =c ^(D)_(Na)

-   -   where    -   c^(I) _(CaMgK): infusate concentration of combined Ca²⁺/Mg²⁺/K⁺    -   c^(I) _(Na): infusate concentration of Na⁺ (optionally added;        e.g. NaCl)    -   c^(D) _(Na): target dialysate Na⁺ concentration    -   c^(D) _(urea): dialysate urea concentration before regeneration    -   η_(CaMgK): exchange efficiency Ca²⁺/Mg²⁺/K⁺ to Na⁺ (approx.        0.85-1)    -   η_(urea): exchange efficiency urea to Na⁺ (<0.1)    -   The optimum concentration c^(I) _(CaMgK) and optimum infusion        ratio may further be determined for the targeted dialysate        composition by empirical iterative optimisation (fine-tuning)

Calculation of Infusion Ratio:

In an idealised analysis, the infusion ratio (ratio of infusate additionflow rate to regenerated dialysate flow rate) is then calculated as

r=v ^(I)/v^(D) =c ^(D) _(CaMgK) /c ^(I) _(CaMgK)

where

-   -   r: infusion ratio    -   v^(I): Infusate addition flow rate    -   v^(D): regenerated dialysate flow rate    -   c^(D) _(CaMgK)=c^(D) _(Ca)+c^(D) _(Mg)+c^(D) _(K) target        dialysate Ca²⁺/Mg²⁺/K⁺ concentration    -   c^(D) _(CaMgK)=c^(I) _(ca)+c^(I) _(Mg)+c^(I) _(K): infusate        Ca²⁺/Mg²⁺/K⁺ concentration

Idealised example:

-   -   c^(D) _(Ca)=3 mEq/L c^(D) _(Mg)=1 mEq/L c^(D) _(K)=3 mEq/L    -   c^(D) _(CaMgK)=7 mEq/L c^(D) _(Na)=138 mEq/L    -   c^(I) _(CaMgK)=c^(D) _(Na)=138 mEq/L    -   r=c^(D) _(CaMgK)/c^(I) _(CaMgK)=7 mEq/L/138 mEq/L≈1:20

An example of the dialysis reconstitution process is illustrated in FIG.16 . In the example illustrated the infusate solution is 51 mL in volumeand includes 3 mEq/L Ca, 1 mEq/L Mg, 3 mEq/L K.

Additional examples with and without addition of NaCl:

-   -   A target dialysate composition    -   c^(D) _(Ca)=3 mEq/L c^(D) _(Mg)=1 mEq/L c^(D) _(K)=3 mEq/L c^(D)        _(Na)=138 mEq/L may be achieved by infusing the following        solution at an infusion ratio of 1:20 c^(I) _(Ca)=59 mEq/L c^(I)        _(Mg)=20 mEq/L c^(I) _(K)=59 mEq/L c^(I) _(Na)=0 mEq/L

The same infusion ratio can be used to produce a dialysate containingc^(D) _(Ca)=2.5 mEq/L c^(D) _(Mg)=1 mEq/L c^(D) _(K)=2 mEq/L c^(I)_(Na)=138 mEq/L if an infusate of the following composition is usedc^(I) _(Ca)=49 mEq/L c^(I) _(Mg)=20 mEq/L c^(I) _(K)=39 mEq/L c^(I)_(Na)=30 mEq/L

Example 10: Full Scale In Vitro Experiment

A full scale experiment according to dialysis circuit 110 shown in FIG.3 was conducted on a simulated patient of 40 L simulated body fluid. Thesorbent composition consisted of the following materials: ZP (1141 g),washed HZO (472 g), AC (160 g), IU (27 g) and sodium carbonate (50 g).The sorbent was dry packed into a container consisting a cylindricalcompartment with inlet and outlet, with filter papers installed beforeand after the sorbent layer. An infusate volume of 4 L was infused over4 h, containing enough salts to reconstitute 72 L of regenerateddialysate during dialysis. The dialysis session was conducted accordingto the parameters in Table 1. The infusion flow rate was 16.7 mL/min andthe dialyate flow rate was 300 mL/min. A blood circuit flow rate of 300mL/min and a simulated blood toxin concentration approximately 1.5 times(assumption of approx. 60% total toxin transfer from the simulatedpatient body fluid to dialysate) the value stated in the description wasused in order to deliver the required toxin challenge to the cartridgein the dialysate circuit. The simulated patient solution thus contained964.5 mmol urea, 40.4 mmol creatinine and 137.4 mmol phosphate in 40L ofsimulated body fluid. Blood upstream of the dialyser was sampled at“blood in”, blood downstream at “blood out” and likewise for thedialysate circuit. As a result of the intrinsic regulation throughmodified sorbent and infusate compositions, a stable sodiumconcentration was observed in both the blood and dialysate circuits forthe duration of the dialysis session (FIG. 5 ).

Statements of Invention

-   1. A sorbent for removing metabolic waste products from a dialysis    liquid, the sorbent comprising a soluble source of sodium ions.-   2. A sorbent as described in statement 1 wherein the soluble source    of sodium ions is a soluble salt.-   3. A sorbent as described in statement 2 wherein the soluble salt is    a basic salt.-   4. A sorbent as described in statement 3 wherein the soluble salt is    selected from one or more of the group consisting of sodium    carbonate, sodium bicarbonate and sodium hydroxide.-   5. A sorbent as described in statement 4 wherein the soluble salt is    sodium bicarbonate.-   6. A sorbent as described in statement 2 wherein the soluble salt is    a neutral salt.-   7. A sorbent as described in statement 6 wherein the sodium salt is    sodium chloride.-   8. A sorbent as described in statement 2 wherein the soluble salt is    a salt of a weak acid.-   9. A sorbent as described in statement 8 wherein the soluble salt is    sodium lactate or sodium acetate.-   10. A sorbent as described in any one of statements 1 to 9, the    sorbent comprising a soluble source of sodium ions in homogeneous    mixture with at least one of: (a) uremic toxin-treating enzyme    particles comprising a uremic toxin-treating enzyme immobilized on a    solid support; (b) cation exchange particles configured to exchange    ammonium ions for predominantly hydrogen ions and to exchange    essential cations predominantly for sodium ions; and (c) anion    exchange particles.-   11. A sorbent as described in statement 10 wherein said cation    exchange particles are set to a pH in the range of from 3.5 to 5.0.-   12. A sorbent as described in statement 11 wherein said cation    exchange particles are set to a pH of about 4.5.-   13. A sorbent as described in any one of statements 10 to 12 wherein    said cation exchange particles have a particle size in the range of    from 10 to 1000 microns, preferably of from 25 to 150 microns, more    preferably of from 50 to 100 microns.-   14. A sorbent as described in any one of statements 10 to 13 wherein    said cation exchange particles comprise an amorphous,    water-insoluble metal phosphate in partially protonated form.-   15. A sorbent as described in statement 14 wherein the metal is    selected from the group consisting of titanium, zirconium, hafnium    and combinations thereof.-   16. A sorbent as described in statement 15 wherein the metal is    zirconium.-   17. A sorbent as described in any one of statements 10 to 16 wherein    said anion exchange particles are set to a pH in the range of from 7    to 14, preferably from 12 to 13.-   18. A sorbent as described in any one of statements 10 to 17 wherein    said anion exchange particles are saturated with a base.-   19. A sorbent as described in statement 18 wherein the base is    selected from the group consisting of sodium hydroxide, sodium    carbonate, sodium bicarbonate, potassium hydroxide, magnesium    hydroxide; calcium hydroxide, ammonium carbonate and ammonium    hydroxide.-   20. A sorbent as described in statement 19 wherein the base is    sodium hydroxide.-   21. A sorbent as described in any one of statements 10 to 20,    wherein said anion exchange particles comprise an amorphous and    partly hydrated, water-insoluble metal oxide in its hydroxide-,    carbonate-, acetate-, and/or lactate-counter-ion form, wherein the    metal may be selected from the group consisting of titanium,    zirconium, hafnium and combinations thereof.-   22. A sorbent as described in statement 21 wherein the anion    exchange particles are zirconium oxide particles.-   23. A sorbent as described in statement 22 wherein the anion    exchange particles are hydrous zirconium oxide particles.-   24. A sorbent as described in any one of statements 10 to 23 wherein    said anion exchange particles have a particle size in the range of    from 10 to 1000 microns, preferably of from 25 to 150 microns, more    preferably of from 50 to 100 microns.-   25. A sorbent as described in any one of statements 10 to 24 wherein    the ratio of cation exchange particle to anion exchange particle is    in the range of from 1:1 to 5:1.-   26. A sorbent as described in statement 25 wherein the ratio of    cation exchange particle to anion exchange particle is in the range    of 2:1 to 3:1.-   27. A sorbent as described in statement 26 wherein the ratio of    cation exchange particle to anion exchange particle is about 2.4:1.-   28. A sorbent as described in any one of statements 10 to 26,    wherein said uremic toxin-treating enzyme particles comprise a    urease.-   29. A sorbent as described in any one of statements 10 to 28,    wherein said uremic toxin-treating enzyme particles have an average    particle size in in the range of from 10 microns to 1000 microns.-   30. A sorbent as described in any one of statements 10 to 29,    further comprising organic compounds absorber particles.-   31. A sorbent as described in statement 30, wherein said organic    compounds absorber particles are activated carbon particles.-   32. A sorbent as described in statement 31, wherein said activated    carbon particles have an average particle size in the range of from    10 microns to 1000 microns.-   33. A sorbent as described in any one of statements 10 to 32 further    comprising a carbonic anhydrase.-   34. A sorbent for removing metabolic waste products from a dialysis    liquid, the sorbent comprising a homogeneous mixture of: (a) uremic    toxin-treating enzyme particles comprising a uremic toxin-treating    enzyme immobilized on a solid support; (b) cation exchange particles    configured to exchange ammonium ions for predominantly hydrogen ions    and to exchange essential cations predominantly for sodium ions;    and (c) anion exchange particles, and further comprising a soluble    source of sodium ions.

35. A sorbent as described in statement 34 wherein the soluble source ofsodium ions is a soluble salt.

-   36. A sorbent as described in statement 35 wherein the soluble salt    is a basic salt.-   37. A sorbent as described in statement 36 wherein the soluble salt    is selected from one or more of the group consisting of sodium    carbonate, sodium bicarbonate and sodium hydroxide.-   38. A sorbent as described in statement 37 wherein the soluble salt    is sodium bicarbonate.-   39. A sorbent as described in statement 35 wherein the soluble salt    is a neutral salt.-   40. A sorbent as described in statement 39 wherein the sodium salt    is sodium chloride.-   41. A sorbent as described in statement 35 wherein the soluble salt    is a salt of a weak acid.-   42. A sorbent as described in statement 41 wherein the soluble salt    is sodium lactate or sodium acetate.-   43. A sorbent as described in any one of statements 34 to 42 wherein    said cation exchange particles are set to a pH in the range of from    3.5 to 5.0.-   44. A sorbent as described in statement 43 wherein said cation    exchange particles are set to a pH of about 4.5.-   45. A sorbent as described in any one of statements 34 to 44 wherein    said cation exchange particles have a particle size in the range of    from 10 to 1000 microns, preferably of from 25 to 150 microns, more    preferably of from 50 to 100 microns.-   46. A sorbent as described in any one of statements 34 to 45 wherein    said cation exchange particles comprise an amorphous,    water-insoluble metal phosphate in partially protonated form.-   47. A sorbent as described in statement 46 wherein the metal is    selected from the group consisting of titanium, zirconium, hafnium    and combinations thereof.-   48. A sorbent as described in statement 47 wherein the metal is    zirconium.-   49. A sorbent as described in any one of statements 34 to 48 wherein    said anion exchange particles are set to a pH in the range of from 7    to 14, preferably from 12 to 13.-   50. A sorbent as described in any one of statements 34 to 49 wherein    said anion exchange particles are saturated with a base.-   51. A sorbent as described in statement 50 wherein the base is    selected from the group consisting of sodium hydroxide, sodium    carbonate, sodium bicarbonate, potassium hydroxide, magnesium    hydroxide; calcium hydroxide, ammonium carbonate and ammonium    hydroxide.-   52. A sorbent as described in statement 51 wherein the base is    sodium hydroxide.-   53. A sorbent as described in any one of statements 34 to 52,    wherein said anion exchange particles comprise an amorphous and    partly hydrated, water-insoluble metal oxide in its hydroxide-,    carbonate-, acetate-, and/or lactate-counter-ion form, wherein the    metal may be selected from the group consisting of titanium,    zirconium, hafnium and combinations thereof.-   54. A sorbent as described in statement 53 wherein the anion    exchange particles are zirconium oxide particles.-   55. A sorbent as described in statement 54 wherein the anion    exchange particles are hydrous zirconium oxide particles.-   56. A sorbent as described in any one of statements 34 to 55 wherein    said anion exchange particles have a particle size in the range of    from 10 to 1000 microns, preferably of from 25 to 150 microns, more    preferably of from 50 to 100 microns.-   57. A sorbent as described in any one of statements 34 to 56 wherein    the ratio of cation exchange particle to anion exchange particle is    in the range of from 1:1 to 5:1.-   58. A sorbent as described in statement 57 wherein the ratio of    cation exchange particle to anion exchange particle is in the range    of 2:1 to 3:1.-   59. A sorbent as described in statement 58 wherein the ratio of    cation exchange particle to anion exchange particle is about 2.4:1.-   60. A sorbent as described in any one of statements 34 to 59,    wherein said uremic toxin-treating enzyme particles comprise a    urease.-   61. A sorbent as described in any one of statements 34 to 60,    wherein said uremic toxin-treating enzyme particles have an average    particle size in in the range of from 10 microns to 1000 microns.-   62. A sorbent as described in any one of statements 34 to 60,    further comprising organic compounds absorber particles.-   63. A sorbent as described in statement 62, wherein said organic    compounds absorber particles are activated carbon particles.-   64. A sorbent as described in statement 63, wherein said activated    carbon particles have an average particle size in the range of from    10 microns to 1000 microns.-   65. A sorbent as described in any one of statements 34 to 64 further    comprising a carbonic anhydrase.-   66. A process of preparing a sorbent comprising mixing a soluble    source of sodium ions and at least one of: (a) uremic toxin-treating    enzyme particles comprising a uremic toxin-treating enzyme    immobilized on a solid support; (b) cation exchange particles    configured to exchange ammonium ions for predominantly hydrogen ions    and to exchange essential cations for sodium ions; (c) anion    exchange particles; and (d) organic compounds absorber particles,    and containing the mixture.-   67. A sorbent which hydrolyses urea to ammonium and bicarbonate, and    binds ammonium predominantly in exchange for protons.-   68. A sorbent which predominantly binds essential cations in    exchange for sodium ions.-   69. A sorbent which (a) hydrolyses urea to ammonium and bicarbonate,    and (b) binds ammonium predominantly in exchange for protons and    binds essential cations predominantly in exchange for sodium ions.-   70. A sorbent cartridge comprising a sorbent as described in any one    of statements 1 to 69 contained within a cartridge.-   71. A dialysis system for treating and recycling dialysate, the    system comprising a sorbent cartridge as described in any one of    statements 1 to 69 which releases a predicted amount of sodium    following ion exchange in the sorbent, a conduit for conveying spent    dialysate from a source of spent dialysate to the sorbent cartridge,    a conduit for conveying regenerated dialysate from the sorbent    cartridge to the source of spent dialysate, and an infusate system    for dosing an infusate solution comprising essential cations to the    regenerated dialysate such that the solution combines with the    predicted release of sodium ions from the sorbent cartridge to    generate a predetermined dialysate sodium concentration.-   72. A dialysis system as described in statement 71 wherein the    essential cations are divalent cations and/or potassium ions.-   73. A dialysis system as described in statement 72 wherein the    divalent cations are calcium and/or magnesium ions.-   74. A dialysis system as described in any one of statements 71 to 73    adapted to keep sodium ion concentration constant in the dialysate.-   75. A dialysis system as described in statement 74 adapted to    produce a concentration of sodium ions of from 132 mEq/L to 145    mEq/L.-   76. A dialysis system as described in in any one of statements 71 to    73 adapted to reduce sodium ion content in regenerated dialysate.-   77. A dialysis system as described in any one of statements 71 to 76    further comprising a source of an osmotic agent for addition to the    regenerated dialysate.-   78. A dialysis system as described in any one of statements 71 to 77    further comprising a source of salts other than calcium, magnesium    and potassium salts for addition to the regenerated dialysate.-   79. A dialysis system as described in statements 78 wherein the salt    other than a calcium, magnesium and potassium salt is sodium    chloride.-   80. A dialysis system as described in any one of statements 71 to 79    wherein the pH of the regenerated dialysate is maintained within a    range of 6 to 8-   81. A process for regenerating dialysate in a dialysis process,    comprising repeating the steps of:-   (a) conveying spent dialysate from a source of spent dialysate to a    sorbent which (a) hydrolyses urea to ammonium and bicarbonate,    and (b) binds ammonium predominantly in exchange for protons and    binds essential cations predominantly in exchange for sodium ions,    to produce regenerated dialysate;-   (b) introducing essential cations to the regenerated dialysate to    reconstitute the dialysate; and-   (c) conveying reconstituted dialysate from the sorbent to the source    of spent dialysate; characterised in that a predetermined    concentration of sodium ions is generated following ion exchange in    the sorbent.-   82. A process as described in statement 81 wherein the sorbent is a    sorbent as described in any one of statements 1 to 65 or 69.-   83. A sorbent which (a) hydrolyses urea to ammonium and bicarbonate,    and (b) binds ammonium predominantly in exchange for protons and    binds essential cations predominantly in exchange for sodium ions,    to produce regenerated dialysate for use in regenerating dialysate    in a dialysis process.-   84. A kit comprising a sorbent as described in any one of statements    1 to 33, 34, or 38 and an infusate comprising salts of essential    ions.-   85. A sorbent as described in either one of statements 4 or 37    wherein the soluble salt is sodium carbonate.-   86. A sorbent as described in any one of statements 1 to 9 wherein    the soluble sodium salt comprises a separate layer or a compartment    in the sorbent.-   87. A sorbent described in either one of statements 33 or 65 wherein    the carbonic anhydrase is immobilised by chemical or physical    bonding to a solid support, or immobilised by cross-linking or    encapsulation.-   88. A dialysis system as described in statement 74 adapted to    produce a concentration of sodium ions of from 120mEq/L to 150    mEq/L.-   89. A dialysis system as described in statement 71 wherein the    concentration of-cation equivalents in the infusate solution is    approximately equal to a predetermined dialysate sodium ion    concentration so that ion exchange in the sorbent, followed by    addition of the infusate solution provides a target dialysate sodium    concentration.-   90. A process as described in statement 81 wherein the essential    cations are introduced as an infusate solution and the concentration    of cation equivalents in the infusate solution is approximately    equal to a predetermined dialysate sodium ion concentration so that    ion exchange in the sorbent, followed by addition of the infusate    solution provides a target dialysate sodium concentration.-   91. A kit as described in claim 84 wherein the infusate is in the    form of an infusate solution in which the concentration of essential    cations is approximately equal to a target sodium ion concentration    or the kit includes instructions to prepare an infusate solution in    which the concentration of essential cations is approximately equal    to a target sodium ion concentration.

1-44. (canceled)
 45. A sorbent for removing metabolic waste productsfrom a dialysis liquid, wherein the sorbent hydrolyses urea to ammoniumand bicarbonate ions, and comprises cation exchange particles set to apH range of from 3.5 to 5.0, and wherein the sorbent binds ammonium ionspredominantly in exchange for protons.
 46. The sorbent according toclaim 45, wherein the sorbent predominantly binds essential cations inexchange for sodium ions.
 47. The sorbent according to claim 46, whereinthe sorbent (a) hydrolyses urea to ammonium and bicarbonate ions, and(b) binds ammonium ions predominantly in exchange for protons and bindsessential cations predominantly in exchange for sodium ions, and whereinthe sorbent comprises cation exchange particles set to a pH range offrom 3.5 to 5.0.
 48. The sorbent according to claim 45, wherein thesorbent is contained within a cartridge.
 49. A dialysis system fortreating and recycling dialysate, the system comprising thesorbent-containing cartridge according to claim 48 and which releases apredicted amount of sodium following ion exchange in the sorbent, aconduit for conveying spent dialysate from a source of spent dialysateto the sorbent cartridge, a conduit for conveying regenerated dialysatefrom the sorbent cartridge to the source of spent dialysate, and aninfusate system for dosing an infusate solution comprising essentialcations to the regenerated dialysate such that the solution combineswith the predicted release of sodium ions from the sorbent cartridge togenerate a predetermined dialysate sodium concentration.
 50. Thedialysis system as claimed in claim 49, wherein: (a) the volume of theinfusate solution to the volume of the dialysate has a volume:volumeratio of from 1:10 to 1:30; or (b) the volume of the infusate solutionto the volume of the dialysate has a volume:volume ratio ofapproximately 1:20 or of approximately 51:1000.
 51. A process forregenerating dialysate in a dialysis process, comprising repeating thesteps of: (a) conveying spent dialysate from a source of spent dialysateto a sorbent, wherein the sorbent is according to claim 45, to produceregenerated dialysate; (b) introducing essential cations to theregenerated dialysate to reconstitute the dialysate using an infusatesolution, wherein the concentration of cation equivalents in theinfusate solution is approximately equal to a target sodium ionconcentration, where the cation equivalents comprise one or more ofcalcium, magnesium, sodium, and potassium; and (c) conveyingreconstituted dialysate from the sorbent to the source of spentdialysate, wherein the reconstituted dialysate is characterised in thata predetermined concentration of sodium ions is generated following ionexchange in the sorbent.
 52. A kit comprising a sorbent as claimed inclaim 45 and an infusate comprising salts of essential ions.
 53. Aninfusate solution for providing a target dialysate sodium concentration,wherein the concentration of cation equivalents in the infusate solutionis approximately equal to a target sodium ion concentration, where thecation equivalents comprise one or more of calcium, magnesium, sodium,and potassium.
 54. A sorbent for removing metabolic waste products froma dialysis liquid, the sorbent comprising a homogeneous mixture of: (a)uremic toxin-treating enzyme particles comprising a uremictoxin-treating enzyme immobilized on a solid support; (b) cationexchange particles configured to exchange ammonium ions for hydrogenions and to exchange calcium, magnesium, and/or potassium cations forsodium ions such that at least 80% of exchanged ammonium ions areexchanged for hydrogen ions, and at least 80% of exchanged calcium,magnesium, and/or potassium cations are exchanged for sodium ions; and(c) anion exchange particles, and further comprising a soluble source ofsodium ions, wherein the cation exchange particles are set to a pH rangeof from 3.5 to 5.0. wherein the soluble source of sodium ions is asoluble salt, and wherein the soluble salt is a neutral salt or a saltof a weak acid.
 55. A process of preparing the sorbent according toclaim 45, the method comprising mixing particles of a soluble source ofsodium ions and: (a) uremic toxin-treating enzyme particles comprising auremic toxin-treating enzyme immobilized on a solid support; (b) cationexchange particles configured to exchange ammonium ions forpredominantly hydrogen ions and to exchange essential cations for sodiumions; (c) anion exchange particles; and (d) organic compounds absorberparticles, wherein the cation exchange particles are set to a pH rangeof from 3.5 to 5.0.